Mapping and characterization of cavitation activity

ABSTRACT

Apparatus for locating bubbles in a subject comprises a plurality of pressure wave detectors arranged to operate as passive detectors to generate output signals in response to the receipt of pressure waves generated at a source comprising at least one bubble, and processing means arranged to receive signals from the detectors and to determine from the signals the position of the source.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority filing benefit of U.S. patentapplication Ser. No. 12/998,571 filed Oct. 19, 2011; International PCTApplication PCT/GB2009/051482 filed Nov. 4, 2009 and published under PCT21(2) in the English language; U.S. Provisional Patent Application Ser.No. 61/111,646 filed Nov. 5, 2008; and Great Britain Patent ApplicationSerial No. 0820377.0 filed Nov. 7, 2008, all of which are incorporatedby reference herein.

FIELD OF INVENTION

The present invention relates to the localization, mapping andcharacterization of bubbles which act as acoustic sources radiatingpressure/density perturbations at any frequency or set of frequencies.It has particular application in the monitoring of therapeuticultrasound treatment but can also be used, for example, in diagnosticultrasound systems and photoacoustic imaging.

BACKGROUND OF THE INVENTION

The use of high intensity focused ultrasound (HIFU) for cancer therapyhas several major advantages over other, more established treatmentmodalities: it is cheap, non-invasive, and has minimal side-effects.However, widespread acceptance of HIFU is hindered by the lack of areliable real-time monitoring system.

Above a certain pressure threshold, high-amplitude acoustic wavespropagating through tissue can spontaneously nucleate and excite small,micron-sized bubbles, a phenomenon known as acoustic cavitation. Thecavitating bubbles re-emit part of the incident ultrasound over a rangeof frequencies that are different to the HIFU excitation frequency,which is useful for two reasons. Firstly, emissions that have a higherfrequency content than the original HIFU source will be absorbed morereadily by surrounding tissue, which means that cavitation can greatlyenhance heat deposition [Coussios C C, Farny C H, Haar G T, Roy R A.“Role of acoustic cavitation in the delivery and monitoring of cancertreatment by high-intensity focused ultrasound (HIFU)”, InternationalJournal of Hyperthermia vol. 23, pp 105-120, 2007]. Secondly, thebroadband acoustic emissions that are associated with this enhancedheating can serve as an indicator of treatment.

Cavitation during HIFU exposure has previously been monitored in eitherof two ways. One option is to use high-frequency broadband transducersto act as passive cavitation detectors (PCDs) that record the acousticemissions from cavitating bubbles [C. H. Farny, R. G. Holt, R. A. Roy,“Monitoring the development of HIFU-induced cavitation activity,” AIPConf. Proc., vol. 829, pp. 348-352, 2006]. PCDs have a fixed focus,however, thereby providing information for a fixed region only. Itshould be noted that there is currently no cavitation monitoring systemthat has been adopted in clinical practice. Alternatively,hyperechogenic regions in B-mode ultrasound images can enable detectionand localization of bubble activity using time-of-flight information [S.Vaezy, et al., “Real-time visualization of high-intensity focusedultrasound treatment using ultrasound imaging”, Ultrasound Med. Biol.,vol. 27, pp. 33-42, 2001]. However, B-mode images can only be takenwhile the HIFU is off to avoid interference from the therapeuticultrasound signal and will thus only enable detection of cavities thatsubsist after HIFU excitation has ceased. B-mode monitoring is thereforeless sensitive than PCD monitoring, and has been previously shown to bedetecting boiling bubbles that are indicative of overtreatment, ratherthan inertially cavitating bubbles that are indicative of enhanced heatdeposition [B. A. Rabkin, V. Zderic, S. Vaezy, “Hyperecho in ultrasoundimages of HIFU therapy: involvement of cavitation,” Ultrasound Med.Biol., vol. 31, pp. 947-956, 2005].

SUMMARY OF THE INVENTION

The present invention provides apparatus for locating bubbles in asubject. The apparatus may comprise a plurality of pressure wavedetectors, which may be sound detectors, arranged to operate as passivedetectors. The detectors may be arranged to generate output signals inresponse to the receipt of pressure waves, which may be in the form ofsound, generated at a source. The source may comprise at least onebubble. The apparatus may further comprise processing means arranged toreceive signals from the detectors and to determine from the signals theposition of the source.

The invention can be used across a broad range of therapeutic,diagnostic and other ultrasound applications, including drug deliverysystems. Some of these are High Intensity Focused Ultrasound (HIFU). Inother applications, for example, in the context of drug delivery,pressure waves with amplitudes that are in-between those used fordiagnostic ultrasound and HIFU are used. Indeed the invention can beused with pressure waves at sound frequencies outside the ultrasoundrange, including audible sound and infra-sound. For example boilingbubbles generated during therapeutic ultrasound treatment can generateaudible sound, which can be detected and used to locate and map thecavitation.

The apparatus may further comprise an ultrasound generator arranged togenerate ultrasound at a generator frequency. The detectors may bearranged to detect ultrasound at least one detection frequency which isdifferent from the generator frequency. The at least one detectionfrequency may comprise a range of detection frequencies, the generatorfrequency being outside the range. The range of frequencies that thedetectors can detect may, for example, be determined by one or morefilters arranged to filter the detector signal. Alternatively, or inaddition, it may be determined by the nature of the detectorsthemselves.

The detectors may be arranged to detect ultrasound while the generatoris active. The processing means may be arranged to determine a positionof the source, which is a position of the source at a time when thegenerator is active.

The generator may be a therapeutic ultrasound generator. The apparatusmay comprise a diagnostic ultrasound generator arranged to generateultrasound at a diagnostic frequency different from the generatorfrequency. The apparatus may comprise an active ultrasound detectorarranged to detect ultrasound at the diagnostic frequency. Thediagnostic generator may be a transducer which also acts as the activeultrasound detector, or it may be a separate generator. The processingmeans may be arranged to receive signals from the active ultrasounddetector.

At least one of the passive ultrasound detectors may be arranged tooperate alternatively as the active ultrasound detector. The passiveultrasound detectors may comprise an array of detectors each of whichcan be operated alternatively as an active ultrasound detector. Thisallows the apparatus to switch between different modes, for example anactive mode and a passive mode, and to use data from both of the modesto locate or characterize the cavitation. This is possible because whatdetermines whether a detector is acting as an active or a passivedetector is at least partly the type of processing that is performed onthe signals from the sensor, as is described in more detail below.Therefore the processing means can be arranged to perform two or moredifferent processing algorithms or methods on the detector signals,which allows the processing means, and therefore the detectors, to beoperated in active or passive modes as required.

The source may comprise a single bubble. The processing means may bearranged to determine the position of the bubble. The processing meansmay be arranged to determine the position of the bubble from the arrivaltimes of ultrasound signals at the detectors.

The source may comprise a plurality of bubbles and the processing meansmay be arranged to process the signals to generate a map of the source.For example the map may be generated by determining an intensity at eachof a plurality of positions from the detector signals using arelationship of the form:

$I = {\frac{1}{T}{\int_{0}^{T}{\left\lbrack {\left( {\sum\limits_{i}{H_{i}(\tau)}} \right)^{2} - {\sum\limits_{i}{H_{i}(\tau)}^{2}}} \right\rbrack\ {\mathbb{d}\tau}}}}$where τ represents a dummy integration variable used to integrate theplurality of signals H_(i)(t), which represent the backpropagatedsignals received from the source(s) by each ultrasound detector, and Trepresents an arbitrary integration time interval.

The processing means may be arranged to turn on the ultrasound generatorand to measure the time at which the detectors detect ultrasound. Theprocessing means may thereby to determine the location of the source.

Indeed the present invention further provides apparatus for locating anultrasound source comprising at least one bubble, the apparatuscomprising an ultrasound transducer and a passive ultrasound detector,and control means arranged to turn the ultrasound transducer on andmeasure the time at which the passive detector detects ultrasoundthereby to determine the location of the source. The transducer may be atherapeutic transducer and may be turned on and off repeatedly duringtreatment of a patient, for example in a duty cycle of 90% or 95%.

The processing means may be arranged to analyze at least two differentfrequency components of the signals to determine a characteristic of thesource. One of the frequency components may be a broadband component.One of the frequency components may include at least one harmonic orsub-harmonic of a generator frequency, and preferably a plurality ofharmonic or sub-harmonic frequencies. The broadband component may beobtained by filtering out components of the detector signals which areat the generator frequency and harmonics of the generator frequency, andoptionally sub-harmonics of the generator frequency also.

The processing means may be arranged to filter out components of thedetector signals at harmonics of the frequency of the generator therebyto produce a filtered signal, and to determine the position of thesource from the filtered signal.

The present invention further provides a method of locating bubbles in asubject, the method comprising receiving ultrasound signals, generatedat a source comprising at least one bubble, at each of a plurality ofpassive ultrasound detectors, generating output signals from each of thedetectors in response to the receipt of the ultrasound, and processingthe signals to determine the position of the source.

Where ultrasound is referred to pressure waves, which may be in the formof sound of other frequencies can also be used where appropriate.

In order to exploit the advantages of both previous approaches, someembodiments of the present invention provide a system that caneffectively act as an array of PCDs that can be electronically focusedin order to provide spatial resolution. In some embodiments the systemis capable of localizing single bubble activity, and in some embodimentsthe system can provide mapping of an extended cavitating region or ofseveral, disjoint cavitating regions.

Preferred embodiments of the present invention will now be described byway of example only with reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of an ultrasound system according to anembodiment of the invention;

FIG. 2 is a schematic diagram of an ultrasound system according to afurther embodiment of the invention;

FIG. 3 is a graph showing a typical signal from one ultrasound detectorforming part of the system of FIG. 2 received from a single-bubblesource;

FIG. 4 is a graph showing arrival estimated time lag of an ultrasoundsignal as a function of position in the detector array of the system ofFIG. 2;

FIG. 5 is a curve fitted to the data of FIG. 4;

FIG. 6 is a mapping of intensity of ultrasound from a single bubble as afunction of distance from the detector array of the system of FIG. 2;

FIG. 7 is a two-dimensional mapping of cavitation produced by the systemof FIG. 2;

FIG. 8 is a two-dimensional mapping of two disjoint cavitation regionsproduced by the system of FIG. 2;

FIGS. 9a and 9b are graphs showing the broadband component of timetraces obtained during HIFU exposure in the system of FIG. 2;

FIG. 10 is a graph showing broadband and harmonic components of thevariance of a signal from one of the detectors in the system of FIG. 2during HIFO exposure; and

FIGS. 11a to 11d are a set of graphs showing passive and activecavitation detection in the system of FIG. 2 using signals received byone of the elements.

FIGS. 12 and 13 each show, for a respective exposure time, images ofinertial cavitation, tissue boiling and tissue damage.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring to FIG. 1, a diagnostic ultrasound system 100 according to afirst embodiment of the invention comprises an array of vibrationdetectors, which in this case are pressure wave detectors arranged todetect sound, specifically ultrasound detectors 102 each of which isarranged to generate an output signal dependent on the amplitude andfrequency of pressure waves it detects, in this case within a range ofultrasound frequencies. The detectors are non-focused, each beingarranged to detect ultrasound signals from a wide range of angles. Eachof the detector output signals is received by a processing system 104which is arranged to process the received signals and to determine fromthem the location of the source of the ultrasound. In this embodimentthe range of ultrasound frequencies which can be detected is 5-10 MHz,but it will be appreciated that this range can vary depending on thesystem. The system in this embodiment is arranged to be used inconjunction with a therapeutic ultrasound system which operates at afrequency range of 500 kHz. This means that the system 100 can be usedto monitor cavitation caused by the therapeutic ultrasound while thetherapeutic ultrasound is being generated. The analysis of the signalsreceived by this system can be the same as the embodiment of FIG. 2, andwill be described in more detail with reference to that Figure.

Referring to FIG. 2, in a second embodiment of the invention anultrasound system 200 comprises a therapeutic ultrasound transducer 201,with an array of ultrasound detectors 202 positioned in an aperture 203in the centre of the transducer 201. Each of the detectors 202 comprisesa transducer which can be operated to generate ultrasonic signals andalso to detect ultrasonic signals. They can therefore be used in anactive mode in which they generate and detect ultrasound signals, or ina passive mode in which they only detect ultrasound signals. The arrayis a linear array extending in a direction which will be referred to asthe x direction as shown in FIG. 2. The direction, perpendicular to thex direction, along the axis of the transducer will be referred to as thez direction. The imaging plane of the array is therefore the x-z plane.The direction perpendicular to both the x and z directions will bereferred to as the y direction.

A control unit 204 is arranged to control generation of ultrasoundsignals by each of the transducer elements 202 and to receive thedetector signals from each of the transducer elements 202 via apre-amplifier and filter block 206. The control unit 204 is alsoarranged to control the transducer 201 to control the power andfrequency of the ultrasound generated by the transducer 201, using asignal from an oscillator 208 to control the frequency of theultrasound. It will be appreciated that the control unit, while beingdescribed functionally, can be made up of a single processor, or two ormore separate processors performing different functions, for examplecontrol and analyzing functions, within the system. The control unit isconnected to a display screen 210 on which data derived from thedetector signals can be displayed in a suitable format. In this case thetherapeutic transducer 201 has a focus in a focal region 214, in whichit will generate the highest intensity ultrasound.

While the arrangement of FIG. 2 can be implemented using a variety ofcomponents and systems that operate over a range of vibrationalfrequencies of sound, including ultrasound, infrasound and audiblesound, in this embodiment a zone system (Zonare Medical Systems, CA),together with the 2008 Research Package, was used as this allowssimultaneous 5 MHz band IQ data acquisition from 64 detector elements202, which can be remodulated to RF. When the array was used in thepassive mode, pulse transmission was switched off so that the array wasacting on receive only. In some modes, one group of transducer elements202 is used in the active mode and another group in the passive mode sothat active and passive detection can be used simultaneously. To makethe system clinically applicable, a modified HIFU transducer 201 (SonicConcepts, Woodinville Wash.) was used that had a central aperture 203for the linear detector array 202 (Zonare L10-5, 5-10 MHz, 38 mmaperture). An IQ band of 4.6-9.6 MHz was chosen for these experiments,the closest possible to the frequency band of the array. This setup isreadily transferable to a HIFU operating unit as no extra space needs tobe made for the array and the orientation between the HIFU transducerand array is fixed.

To evaluate the system's ability to localize and map cavitation, severalHIFU operating regimes and tissue mimicking gels were used. Here two ofthese will be described. Firstly, a homogeneous 3% aqueous agar gel wasprepared. The water was deionized and the mixture was degassed at −50kPa for 30 minutes. Upon setting, the gel was exposed to 1.06 MHz HIFU(Sonic Concepts H-102B SN-22) at its cavitation threshold of 1.1 MPapeak negative pressure at the focus, so that a single cavitating sourcewould be created.

Secondly, in order to get two known regions of cavitation, a similar gelwas made but with two 1.6 mm channels running parallel and at a distanceof 20 mm from each other. The channels were positioned so that they cutacross the linear array's imaging plane, making two 1.6 mm diametercircles, and these circles were along the axis of the HIFU transducer201 (500 kHz, Sonic Concepts H-107B SN-10), being 10 mm in front of, and10 mm behind the HIFU focus. 0.5% talc solution was made to flow throughboth channels, which cavitates much more readily than agar. A 500 kHztransducer was chosen because the pressure does not drop significantlyover a distance of 10 mm, so when driving the transducer at 0.6 MPa peaknegative focal pressure, the cavitation threshold of agar is notexceeded (1.1 MPa at 500 kHz), while the threshold for talc solution(0.2 MPa at 500 kHz) is.

The theory behind the operation of the two embodiments of the inventionwill now be described. Active detection, which includes pulse-echoimaging, requires an ultrasound generator which is arranged to generateultrasound, typically in a pulse, and an ‘active’ detector’ whichdetects reflected or re-emitted ultrasound from a cavitation region, anda processing system which uses the time interval between the generationof the ultrasound and the detection of ultrasound in determining theposition of detected cavitation. In contrast, in passive localizationand mapping, there is no direct information about the propagation timefrom a source to a receiver. Instead, cross-correlation of signals froma pair of receivers can provide an estimate of the differential time ofarrival (DTOA), i.e., the difference in arrival time at the receivers ofa signal from a source. This enables the difference in distance betweenthe receivers and the source to be estimated. By using a set ofcross-correlation pairs, single source localization and extended sourcemapping is possible. It will be appreciated from this that a singledetector can be operated in both active and passive detection, dependingon the processing which is performed on the sensor signals. A furtherexplanation of passive localization and imaging follows.

Single Bubble Localization

Take a linear array of detector elements focused in the y=0 plane andplaced on the x-axis, with receivers at x₁, x₂, . . . x_(N). The regionof interest for cavitation localization is in front of the array: y=0,x₁<x<x_(N), z>0. Suppose there is a single cavitating source at aposition (x_(s),z_(s)). The propagation distance from the source to anelement at x, relative to the distance between the source and areference element at x₀ is then[z _(s) ²+(x−x _(s) ²)]^(1/2) −[z _(s) ²+(x ₀ −x _(s) ²)]^(1/2).  (1)

Assuming linear propagation of sound with speed c, we use the Fresnelapproximation to derive the time of arrival of the source to an elementat x relative to the time of arrival to the reference element at x₀:1/c·(αx ² +βx+γ),  (2)where

α=−1/(2z_(s));β=x _(s) /z _(s);  (3)

γ=(x₀ ²−2x₀x_(s))/(2z_(s)).

The above expressions lead to a simple and efficient algorithm forlocalizing a single source, which includes the following steps:

-   -   1. Calculate the differential times of arrival between elements        at various positions x and a reference element x₀ using        cross-correlations.    -   2. Fit a parabola (using least square error linear fitting) to        the differential times of arrival, extracting the parabolic        coefficients α, α, γ.    -   3. Use equation (3) to calculate source location (x_(s),z_(s))        from α, α.        Extended Cavitation Region Mapping

When there is an extended region of cavitation, spatial maps ofcavitation are necessary. The approach taken in this embodiment of theinvention is one of passive beamforming, namely Time Exposure Acoustics(TEA) used in passive seismic imaging [S. J. Norton, B. J. Carr, A. J.Witten, “Passive imaging of underground acoustic sources,” J. Acoust.Soc. Am., vol. 119, pp. 2840-2847, 2006.] A summary of the algorithmfollows. Assume we have a source field s(x,z,t) with zero temporal mean,that causes the pressure field p(x,z,t) to propagate according to thelinear wave equation:

$\begin{matrix}{{{{\nabla^{2}p} - {\frac{1}{c^{2}}\frac{\partial^{2}p}{\partial t^{2}}}} = {- {s\left( {x,z,t} \right)}}},} & (4)\end{matrix}$

To estimate the source intensity I (temporal mean of s squared) at aposition (x_(s),z_(s)), the RF pressure signal p_(i)(t) for each elementi of the array is back-propagated, and the following combination oftemporal and ensemble moments taken:

$\begin{matrix}{{I = {\frac{1}{T}{\int_{0}^{T}{\left\lbrack {\left( {\sum\limits_{i}{H_{i}(\tau)}} \right)^{2} - {\sum\limits_{i}{H_{i}(\tau)}^{2}}} \right\rbrack\ {\mathbb{d}\tau}}}}},} & (5)\end{matrix}$where H_(i)(τ) is the back-propagated signalH _(i)(τ)=d _(i) ·p _(i)(t+d _(i) /c+τ),  (6)where τ is a dummy integration variable and τ is an arbitraryintegration time interval with d being the propagation distance from thepoint (x_(s),z_(s)) to array element i:d _(i) =[z _(s) ²+(x−x _(s) ²)]^(1/2).  (7)Using the identity

$\begin{matrix}{{{\left( {\sum\limits_{i}a_{i}} \right)^{2} - {\sum\limits_{i}a_{i}^{2}}} = {2{\sum\limits_{i < j}{a_{i}a_{j}}}}},} & (8)\end{matrix}$and changing the order of summation and integration, the intensity map Ican be re-arranged to give

$\begin{matrix}{I = {\sum\limits_{i < j}{\left\lbrack {\frac{2}{T}{\int_{0}^{T}{{H_{i}(\tau)}{H_{j}(\tau)}\ {\mathbb{d}\tau}}}} \right\rbrack.}}} & (9)\end{matrix}$

Equation (9) shows that the intensity map also corresponds to summingover all pairs of cross-correlations of back-propagated signalsH_(i)(τ)—however, calculation of the intensity from (5) iscomputationally more efficient. It should also be noted that in additionto compensation of spherical spreading and propagation time, H_(i)(τ)can be filtered to deconvolve the receiver response, to whiten thesignal in order to give sharper cross-correlations, or to apply atomographic filter to compensate for frequency-dependent blurring.However, in the example described above filtering the signal caused nosignificant changes to the maps, as the signal was band-limited asdescribed above.

FIG. 3 shows a segment of an RF trace reconstructed from IQ data(4.6-9.6 MHz) from one of the detector elements 202 when the homogeneousagar phantom was insonified at its cavitation threshold. A periodiccavitation signal, corresponding to every third period of the 1.06 MHzcycle, can be clearly seen on each of the 64 detector elements, fromwhich the presence of a single source can be inferred. Takingcross-correlations of the signal from a reference element with thesignals from each of the 64 detector elements provides an indication ofthe delay in the signal from the source reaching each of the detectorelements, and reveals a curved delay profile over the detector elementarray as shown in FIG. 4, to which a parabola can be fitted, as shown inFIG. 5. This profile can be used to determine the position of thesource, using equation (3) as described above. In this example thesource is located at 73.7 mm from the array, and −2.1 mm along thearray. This is in agreement with where the 1.06 MHz HIFU focus wasmeasured to be relative to the linear array using B-mode ultrasound.

In order to investigate the spatial resolution that can be achieved witha passive array, the algorithm for extended cavitation region mappingwas applied to the case of a single-bubble source. Note that lateralresolution is significantly better than axial resolution, so FIG. 6shows an axial cross-section of the intensity map, of single bubble datausing time exposure acoustics (TEA), i.e., equation (9) above, togetherwith a simulation of the map.

The simulation took a single bubble RF recording as the source, placedthe source at the position estimated by the parabolic localizationalgorithm (−2.1,73.7) mm, and propagated the signal to the arrayelements. A source intensity map was then generated using TEA from thisdata. The solid line shows a map generated from actual single bubblerecordings, while the dashed graph shows a simulated map. Note thatbecause axial resolution is inversely proportional to axial distancesquared (not proved here), much higher resolved maps could be generatedby placing the array closer to the agar phantom. However, such a setupwould no longer be clinically applicable.

The algorithm for extended cavitation region mapping was also applied toan extended cavitating region during HIFU exposure. The resultingintensity map is shown in FIG. 7, where it can be seen that the mappedcavitation region corresponds extremely well with the region over whichthe pressure amplitude generated by the HIFU transducer exceeds thecavitation threshold (continuous black line).

Finally, in the homogeneous two-channel phantom, cavitation wassuccessfully instigated in the talc solution, creating two disjointcavitation regions in the imaging plane. A passive map of this generatedusing (9) is shown in FIG. 8, in which the positions at which thechannels intersect the image plane are indicated by the dashed circlesand the cavitation can be seen as lighter areas in the region of thechannels.

This embodiment therefore provides a system that can successfully locatea single cavitating source. More importantly, the setup allows mappingof spatially distributed cavitation while the HIFU signal is on. Thisprovides a novel method of HIFU treatment monitoring that offers severaladvantages over currently used B-mode hyperechogenicity imaging.

It will be appreciated that the system of FIG. 1 can operate in the samepassive modes as the system of FIG. 2, and can detect cavitation caused,for example, by a separate therapeutic transducer, or cavitation causedby other means.

In the context of non-invasive cancer therapy by HIFU, the occurrence ofinertial cavitation can potentially be highly beneficial under moderateHIFU exposure conditions, since it can result in greatly enhanced ratesof heat deposition. By contrast, the occurrence of stable cavitation,and in particular of larger, thermally induced bubbles, can bedetrimental as it may result in asymmetric (or ‘tadpole-shaped’) lesionformation, overtreatment and undesirable prefocal damage. It istherefore beneficial to be able to characterize bubble activity duringHIFU exposure, as well as to locate it as described above.

All types of bubble activity re-radiate part of the incident HIFU fieldat frequencies far removed from the main HIFU excitation frequency,making it possible to detect and qualify cavitation via spectralanalysis of the noise emissions acquired passively during HIFU exposure.In particular, the onset of inertial cavitation is associated with asudden increase in broadband noise, whilst larger cavities oscillatingstably will result in increased emissions at harmonics, subharmonics andsuperharmonics of the main HIFU excitation frequency (collectivelyqualified as ‘harmonics’ hereafter). Furthermore, certain types ofbubble activity induce a change in the local characteristic impedance ofthe target medium, resulting in a well-documented increase in thescattering and reflection of an actively generated incident diagnosticpulse that has become known as ‘hyperecho’ in B-mode images [Rabkin, B.A., et al., Biological and physical mechanisms of HIFU-induced hyperechoin ultrasound images. Ultrasound in Medicine & Biology, 2006. 32(11): p.1721-1729].

The system of FIG. 2 is therefore arranged in one operating mode tocombine passive and active cavitation detection schemes to providereal-time detection, classification, and localization of cavitationactivity.

In this mode, the HIFU transducer 201 is driven at a 95% duty cycleusing a function generator (Agilent 33220A) and a 55 dB fixed gain poweramplifier (Electronics and Innovation A300). To test this mode, apolyacrylamide-based tissue-mimicking material containing dissolvedbovine serum albumin was used as the target [Lafon, C, et al., Gelphantom for use in high-intensity focused ultrasound dosimetry.Ultrasound in Medicine and Biology, 2005. 31(10): p. 1383-1389]. Inorder to enable co-axial cavitation detection during HIFU exposure, ahigh-frequency, single-element diagnostic transducer (Panametrics V319)was placed inside the central opening of the HIFU transducer andpositioned so that its focus overlaps with that of the therapytransducer. The diagnostic transducer is driven in pulse-echo mode usinga pulser-receiver (JSR Ultrasonics DPR300) ensuring that the transmittedpulse is incident upon the HIFU focal region during the 5% off-time ofthe HIFU excitation. It will be appreciated that the 95% duty cycleenables the therapeutic HIFU transducer to be active for most of thetime, with the 5% off time allowing for passive cavity detection andalso ‘pseudo active’ cavity detection in which time of flightinformation can be determined for the passive detectors using the knowntime at which the therapeutic transducer 201 is turned on. The delaybetween that turn-on time and the first passive detection of cavitationat each of the detectors can be determined and used to determine theposition of the cavitation events. It will be appreciated that one ormore of the transducer elements 202 of the system of FIG. 2 can be usedin a passive mode to operate in the same way.

A 400-microsecond time trace of the signal received by the axialcavitation detector was recorded every 50 ms throughout the HIFUexposure, the first 200 microseconds coinciding with the HIFU off-time,and the last 200 microseconds with the HIFU on-time. This makes itpossible to utilize a single trace to reap the benefits of both anactive and a passive detection scheme. The active scheme enableslocalization of bubble clouds by tracking the position of largereflections of the transmitted pulse. The passive scheme also providesinformation as to the position of the bubble cloud front nearest to theHIFU transducer, which can be identified by tracking the time-of-flightof the leading edge of the passively received signal, timed from theknown time at which the HIFU transducer is turned on. More importantly,however, the passive scheme also enables classification of the type ofcavitation activity being detected by using the spectral analysistechnique described below.

In order to distinguish between the presence of inertial and stablecavitation, a Fast Fourier Transform (FFT) or similar spectral analysisalgorithm is applied to each passively received signal, which enablesseparation of its harmonic and broadband noise components by digitalfiltering. This is achieved by applying bandpass filters of bandwidth0.18 MHz around all multiples and sub-multiples of the HIFU excitationfrequency: taking an inverse FFT of this signal provides the ‘harmonic’time trace that only captures activity due to stable cavitation and, toa lesser extent, non-linear propagation through the phantom (the latterwas not found to be significant in the tissue-mimicking material in theabsence of bubbles). The signal remaining after applying 0.18 MHz notchfilters to the original signal to remove the harmonics of the excitationfrequency is purely representative of broadband noise. Similarly, itsinverse FFT therefore provides a ‘broadband’ time trace that solelycaptures inertial cavitation activity.

Prior to experimentation, the inertial cavitation threshold in thetissue phantom was determined and found to be in the region of 1.5 MPapeak negative focal pressure. All pressures used in subsequent exposureswere chosen to be well above this value.

Results

Passive Location Scheme

The principle of location of inertial cavitation activity using apassive detection scheme is illustrated in FIGS. 9a and 9b , which showsthe time traces corresponding to the broadband component of thepassively received signal during 1.1 MHz HIFU exposure of a tissuephantom at two different peak negative pressure amplitudes, chosen to begreater than the cavitation threshold.

The overlaid continuous line with a set of rounded peaks represents theaxial pressure profile of the HIFU transducer measured using ahydrophone in water, whilst the leftmost dotted vertical line indicatesthe position of the phantom edge nearest to the HIFU transducer. Thex-axis is converted into relative axial distance by using the speed ofsound through the phantom and the square markers indicate the earliestoccurrence of inertial cavitation activity. At the lower peak negativefocal pressure amplitude (1.92 MPa), which is close the cavitationthreshold, inertial cavitation activity is seen to onset at the positionof maximum HIFU pressure. However, at the higher pressure amplitude(2.86 MPa), inertial cavitation is seen to onset some 10 mm ahead of theHIFU focus.

Passive Detection—Based Classification of Cavitation Activity

Continuous monitoring of the variance of passively received noiseemissions during HIFU exposure provides a good indication of theevolution of bubble activity. Application of the digital filteringtechniques described above prior to computing this variance makes itpossible to qualify the different types of cavitation activity duringHIFU exposure. This is illustrated in FIG. 10, which shows the broadbandand harmonic components of the original, unfiltered passively receivedsignal over time. At this high peak negative pressure amplitude (8.3MPa), the broadband noise emissions associated with inertial cavitationactivity occur immediately, but decay rapidly. This is most probably dueto heat deposition in the phantom resulting in an increase in vapourpressure that inhibits bubble collapse. By contrast, stable cavitationactivity is present throughout the exposure but increases dramaticallybeyond 4 seconds. This is likely due to the formation of boiling bubblesdue to excessive heating of the phantom, which result in a sharpincrease in the harmonic component of the passively received signal.

Combined Passive-Active Cavitation Detection

Lastly, the benefits of combining active and passive localizationtechniques are illustrated in FIGS. 11a to 11d . FIGS. 11a and 11b bothshow the variance of the passively received signal during a 30 secondHIFU exposure (starting at t=2 s) at 3.5 MPa peak negative focalpressure. FIGS. 11c and 11d show the corresponding active trace at twodifferent time instants over the course of the HIFU exposure, indicatedby arrows on the passive trace in FIGS. 11a and 11b respectively. Att=2.80 s, passively detectable emissions are clearly present, but thereis no signal detectable on the active trace. At t=5.05 s, the passivelydetectable emissions are considerably higher than at t=2.80 s, but thereis now a large reflection visible on the active trace from the regioncoincident with the HIFU focus. The active scheme therefore seems moreeffective at detecting and localizing stable cavitation activity thattends to occur in the latter stages of HIFU exposure, whilst the passivescheme provides a more reliable indicator of inertial cavitationactivity. Therefore, a combined active and passive system cancharacterize the detected cavitation as well as locating it.

In order to demonstrate the effectiveness of passive imaging using anembodiment of the present invention, referring to FIG. 12, the top imageis a cumulative passive broadband map indicative of inertial cavitationactivity, the middle image is a cumulative passive harmonic mapindicative of tissue boiling, and the bottom image is an image ofhistological damage in tissue, all following a 2-second ablativeexposure of bovine liver tissue at a therapeutic ultrasound frequency of1.1 MHz and at an intensity of 4 kW cm⁻² from the left. ‘0’ on thex-axis indicates the predicted focus location of the therapeuticultrasound beam. It can be seen that the passive mapping of broadbandemissions successfully predicts the size and location of the resultingthermal lesion. The null harmonic map confirms the absence of boilingbubbles during this exposure.

Referring to FIG. 13, similar images are shown for a 10-second exposure.It can be seen that the passive mapping technique successfully describesthe movement of the thermal lesion towards the HIFU transducer. The‘pitting’ visible inside the thermal lesion is also consistent with thepresence of boiling bubbles, which have been successfully predicted byharmonic mapping. It will be appreciated that the system of FIG. 2 canoperate in a number of different modes, either passive only to providesingle bubble location or mapping of a region of cavitation, and incombined passive and active modes to characterize cavitation at the sametime as locating or mapping it. Importantly, the system of FIG. 2 canlocate or map, and therefore provide an image of or analyse, cavitationas it occurs during therapeutic ultrasound treatment.

In a further embodiment rather than a single array of detector elementsthat can be used as active or passive elements, in other embodimentsthere is an array of active elements and an array of passive elements.This provides the same range of operating modes.

In a further embodiment, a system similar to that of FIG. 2 can be usedto control drug delivery or drug activity. It has been shown thatacoustic vibration can greatly enhance the take-up and effect of variousdrugs, and the location, mapping, and characterization of bubbles insuch applications is an important application of systems such as that ofFIG. 2.

The invention claimed is:
 1. Apparatus for locating a source of pressurewaves, the source being located at a position in a subject, the sourcecomprising at least one bubble, the apparatus comprising a pressure wavetransducer configured to generate pressure waves at a generationfrequency to generate cavitation including the at least one bubble, anarray of pressure wave detectors configured to operate as passivedetectors to generate output signals in response to the receipt of thepressure waves generated at the source over a broadband range offrequencies including harmonic components at harmonics of the generationfrequency, and a processor configured to: receive the output signalsfrom the detectors and determine from the signals the position of thesource, following a removal of the harmonic components using filtering.2. Apparatus according to claim 1 wherein the detectors are configuredto detect pressure waves while the transducer is active and theprocessor is configured to determine the position of the source, whichis the position of the source at a time when the transducer is active.3. Apparatus according to claim 1 wherein the transducer is atherapeutic sound generator and the apparatus comprises a diagnosticpressure wave generator configured to generate pressure waves at adiagnostic frequency different from the generation frequency. 4.Apparatus according to claim 3 comprising an active pressure wavedetector configured to detect pressure waves at the diagnosticfrequency.
 5. Apparatus according to claim 4 wherein the diagnosticpressure wave generator is a transducer which also acts as the activepressure wave detector.
 6. Apparatus according to claim 4 wherein theprocessor is configured to receive signals from the active pressure wavedetector.
 7. Apparatus according to claim 5 wherein at least one of thepassive pressure wave detectors is configured to operate alternativelyas the active pressure wave detector.
 8. Apparatus according to claim 7wherein each of the passive pressure wave detectors is arranged to beoperated alternatively as an active pressure wave detector.
 9. Apparatusaccording to claim 1 wherein the source comprises a single bubble. 10.Apparatus according to claim 9 wherein, if the pressure waves arrive atthe detectors at respective arrival times, the processor is configuredto determine the position of the bubble from the arrival times ofpressure waves at the detectors.
 11. Apparatus according to claim 1wherein the source comprises a plurality of bubbles and the processor isconfigured to process the signals to generate a map of the source. 12.Apparatus according to claim 11 wherein the processor is configured togenerate the map by determining an intensity at each of a plurality ofpositions from the detector signals using a relationship of the form:$I = {\frac{1}{T}{\int_{0}^{T}{\left\lbrack {\left( {\sum\limits_{i}{H_{i}(\tau)}} \right)^{2} - {\sum\limits_{i}{H_{i}(\tau)}^{2}}} \right\rbrack\ {\mathbb{d}\tau}}}}$where τ represents a dummy integration variable used to integrate theplurality of signals H_(i)(t), which represent the backpropagatedsignals received from the source(s) by each pressure wave detector, andT represents an arbitrary integration time interval.
 13. Apparatusaccording to claim 1 wherein the processor is configured to turn on thepressure wave transducer and to measure the time at which the detectorsdetect pressure waves, thereby to determine the location of the source.14. Apparatus according to claim 1 wherein the processor is configuredto analyse at least two different frequency components of the signals todetermine a characteristic of the source.
 15. Apparatus according toclaim 14 wherein one of the frequency components is a broadbandcomponent, and one of the frequency components includes at least oneharmonic of a generator frequency.
 16. Apparatus for locating a sourceof pressure waves, the source being located at a position in a subject,the source comprising at least one bubble, the apparatus comprising anarray of pressure wave detectors configured to operate as passivedetectors to generate output signals in response to the receipt of thepressure waves generated at the source, and a processor configured toreceive the output signals from the detectors, to perform a crosscorrelation between the signals from a pair of the detectors bymultiplication and integration of the signals from said pair ofdetectors, and to determine from the signals the position of the sourceusing the cross correlation.
 17. Apparatus according to claim 16 furthercomprising a pressure wave generator configured to generate pressurewaves at a generator frequency, wherein the detectors are configured todetect pressure waves at least one detection frequency which isdifferent from the generator frequency.
 18. Apparatus according to claim17 wherein the detectors are configured to detect pressure waves whilethe generator is active and the processor is configured to determine theposition of the source, which is the position of the source at a timewhen the generator is active.
 19. Apparatus according to claim 17wherein the generator is a therapeutic sound generator and the apparatuscomprises a diagnostic pressure wave generator configured to generatepressure waves at a diagnostic frequency different from the generatorfrequency.
 20. Apparatus according to claim 16 wherein the sourcecomprises a plurality of bubbles and the processor is configured toprocess the signals to generate a map of the source.
 21. Apparatus forlocating source of pressure waves, the source being located at aposition in a subject, the source comprising at least one bubble, theapparatus comprising an array of pressure wave detectors configured tooperate as passive detectors to generate output signals in response tothe receipt of the pressure waves generated at the source, and aprocessor configured to: receive the output signals from the detectors;and determine from the signals the position of the source using a squareof each of the signals.
 22. Apparatus according to claim 21 furthercomprising a transducer arranged to generate pressure waves at ageneration frequency, wherein the detectors are configured to detectpressure waves while the transducer is active and the processor isconfigured to determine the position of the source, which is theposition of the source at a time when the transducer is active. 23.Apparatus according to claim 22 wherein the transducer is a therapeuticsound generator and the apparatus comprises a diagnostic pressure wavegenerator configured to generate pressure waves at a diagnosticfrequency different from the generation frequency of the transducer. 24.Apparatus according to claim 21 wherein the source comprises a pluralityof bubbles and the processor is configured to process the signals togenerate a map of the source.
 25. Apparatus according to claim 21wherein the processor is configured to generate the map by determiningan intensity at each of a plurality of positions from the detectorsignals using a relationship of the form:$I = {\frac{1}{T}{\int_{0}^{T}{\left\lbrack {\left( {\sum\limits_{i}{H_{i}(\tau)}} \right)^{2} - {\sum\limits_{i}{H_{i}(\tau)}^{2}}} \right\rbrack\ {\mathbb{d}\tau}}}}$where τ represents a dummy integration variable used to integrate theplurality of signals H_(i)(t), which represent the backpropagatedsignals received from the source(s) by each pressure wave detector, andT represents an arbitrary integration time interval.
 26. Apparatus forlocating a pressure wave source comprising at least one bubble locatedat a position in a subject, the apparatus comprising a therapeuticpressure wave transducer configured to generate therapeutic pressurewaves at a generation frequency to generate cavitation including the atleast one bubble, a passive pressure wave detector arranged to detect afirst arrival at the detector, at a first arrival time, of the pressurewaves generated at the source and of a frequency which is different fromthe generation frequency and harmonics thereof, and output a signal inresponse to the pressure waves generated at the source, a display, and acontroller configured to: turn the pressure wave transducer on; receivethe signals from the detectors; process the signal to identify a leadingedge of the signal; determine the delay between the time at which thetherapeutic pressure transducer was turned on and the first arrivaltime; determine, from said delay, the location of the source; andcontrol the display to indicate the location of the source.
 27. Theapparatus according to claim 26 further comprising at least one furtherdetector, each said further detector being arranged to output arespective further signal in response to the pressure waves generated atthe source, wherein the controller is configured to receive each saidfurther signal, and to identify a further leading edge in each saidfurther signal.
 28. The apparatus according to claim 26 furthercomprising a filter arranged to remove components of the signal at thetransmission frequency prior to processing the signal to identify saidleading edge.
 29. A method of locating a pressure wave source comprisingat least one bubble located at a position in a subject, the methodcomprising: providing a pressure wave transducer arranged to generatetherapeutic pressure waves at a generation frequency to generatecavitation including the at least one bubble, turning the pressure wavetransducer on at a turn on time thereby to generate cavitation includingthe at least one bubble in the subject; detecting a first arrival at thedetector, at a first arrival time, of the pressure waves generated atthe source and of a frequency which is different from the generationfrequency and harmonics thereof, and determining the delay between theturn on time and the first arrival time thereby to determine thelocation of the source.
 30. The method according to claim 29 furthercomprising providing a passive pressure wave detector, receiving thepressure waves generated at the source and generating a signal inresponse to the pressure waves generated at the source using thedetector, and wherein detecting said first arrival comprises identifyinga leading edge in the signal.
 31. The method according to claim 29wherein the cavitation is inertial cavitation.